This invention relates to the field of drug delivery devices which incorporate a rate controlling membrane in order to control the rate of release of a drug from the device to a patient. More particularly, the invention is directed to rate controlling membranes for drug delivery devices characterized by being subjected to an annealing process in accordance with the present invention. The rate controlling membranes of this invention exhibit improved membrane functionality particularly with respect to storage time.
The use of rate controlling membranes to control delivery of a drug from a drug delivery device is well known. For example, transdermal drug delivery devices including rate controlling membranes are disclosed in U.S. Pat. Nos. 3,797,494, 4,031,894, 4,201,211, 4,379,454, 4,436,741, 4,588,580, 4,615,699, 4,661,105, 4,681,584, 4,698,062, 4,725,272, 4,832,953, 4,908,027, 5,004,610, 5,310,559, 5,342,623, 5,344,656, and 5,364,630, which are incorporated in their entirety herein by reference. As disclosed in these patents, various materials, including ethylene vinyl acetate copolymers and polyethylene, may be used to form rate controlling membranes useful for transdermal drug delivery systems. Additional materials useful for forming rate controlling membranes for transdermal drug delivery devices are disclosed in K. P. R. Chowdary et al. xe2x80x9cPreparation and Evaluation of Cellulose Acetate Films as Rate Controlling Membranes for Transdermal Usexe2x80x9d Indian Drugs 29 (7).
For a selected membrane material, after conversion of the polymer pellet to the membrane, the necessary rate control for a transdermal drug delivery device is provided by varying the composition, pore size, or thickness of the rate controlling membrane, adjusting the viscosity of the drug formulation to be administered by appropriate formulation, or impregnating the pores of the membranes with a diffusive medium as disclosed in U.S. Pat. No. 3,797,494 listed above. The rate controlling membrane is then incorporated into a transdermal drug delivery device without any other additional treatment thereof.
Diffusional and osmotically driven fluid-imbibing dosage forms incorporating rate controlling membranes are also known in the art. For example, U.S. Pat. Nos. 3,845,770 and 3,916,899, incorporated herein by reference, disclose a device comprising a wall that surrounds a compartment containing a drug for delivery to a patient. The wall of the device is permeable to the passage of fluid. Drug is released from the device by fluid being imbibed through the wall into the device at a rate determined by the permeability of the wall and the osmotic pressure gradient across the wall. Other diffusional and osmotic fluid-imbibing dosage forms are disclosed in U.S. Pat. Nos. 3,987,790, 4,111,202, 4,111,203, 4,203,439, 4,327,725, 4,612,008, 4,865,845, 5,034,229, 5,057,318, 5,059,423, 5,110,596, 5,112,614, 5,137,727, 5,234,692, and 5,234,693, all of which are hereby incorporated in their entirety by reference.
Additionally, U.S. Pat. Nos. 4,931,285, 5,024,842, and 5,160,743 disclose a dosage form comprising a coat surrounding a drug. The coat comprises a water soluble overcoat polymer and a subcoat. The overcoat and the subcoat are annealed to provide a continuous, insoluble membrane or film that surrounds the drug and which dissolves in an aqueous environment of use.
One problem associated with prior art rate controlling membranes formed from thermoplastic polymers is that they often encounter morphological changes after processing over long periods of time due to phase separation of domain structures. These morphological changes can alter the membrane functionality. For example, the water permeation or water uptake rate through the membrane of fluid-imbibing devices may vary over time, leading to inconsistent performance of the device.
Another problem associated with prior art rate non-annealed rate controlling membranes used in controlled drug delivery devices is that the permeability of the membrane may vary over the storage period, particularly when such devices are exposed to elevated temperatures. If this occurs, the system would not have a drug release rate which is stable as a function of storage time. This is particularly undesirable where, for example, the permeability of the rate controlling membrane to the drug is increased beyond a preferred range due to exposure of the system to elevated temperatures.
Variations in the rate of administration of drugs can effect efficacy and cause undesirable side effects. As can be appreciated by one of ordinary skill in the art, variations in the functionality of rate controlling membranes of drug delivery devices over storage may arise in any device which incorporates a rate controlling membrane and can pose a significant problem.
As used herein, the term xe2x80x9cdrugxe2x80x9d is to be construed in its broadest sense to mean any material which is intended to produce some biological, beneficial, therapeutic, or other intended effect, such as permeation enhancement, for example, on the organism to which it is applied.
As used herein, the term xe2x80x9cindividualxe2x80x9d intends a living mammal and includes, without limitation, humans and other primates, livestock and sports animals such as cattle, pigs and horses, and pets such as cats and dogs.
As used herein, the term xe2x80x9cmembrane functionalityxe2x80x9d refers to properties of the membrane which affect the desired degree of rate control of the drug delivery device in which the membrane is used and includes for example, drug permeability, water permeability, and/or water uptake.
As used herein, the term xe2x80x9ctransdermalxe2x80x9d intends both percutaneous and transmucosal administration, i.e., passage of drug through skin or mucosal tissue into the systemic circulation.
According to this invention, rate controlling membranes intended for use in controlled drug delivery devices are pretreated by an annealing process prior to or subsequent to incorporation of the membrane into the drug delivery device. The annealing process of this invention provides rate controlling membranes which exhibit consistent membrane functionality over time. In one embodiment, the annealed rate controlling membranes of this invention comprise enhanced permeability compared to non-annealed membranes that is more predictable with respect to thermal transients, particularly throughout storage over time. According to another embodiment, rate controlling membranes subjected to the annealing process of this invention maintain a permeability within a preferred range even after being subjected to elevated temperatures.
Accordingly, it is an aspect of this invention to provide rate controlling membranes for use in controlled drug delivery devices that overcome the disadvantages associated with those of the prior art.
Another aspect of the invention is to provide rate controlling membranes which exhibit consistent membrane functionality over time.
Another aspect of this invention is to provide rate controlling membranes for transdermal drug delivery systems that have more predictable drug permeabilities with respect to thermal transients.
Another aspect of this invention is to provide rate controlling membranes for transdermal drug delivery devices that have drug permeabilities that are stable as a function of storage time.
Another aspect of this invention to provide rate controlling membranes for transdermal drug delivery devices that provide enhanced drug permeability.
Yet another aspect of this invention is to provide rate controlling membranes for fluid-imbibing drug delivery devices which exhibit consistent water permeability and water uptake over a storage period.
Therefore, the invention comprises the following aspects, either alone or in combination:
A rate controlling membrane for a controlled drug delivery device characterized by being subjected to an elevated temperate of about 300xc2x0 C. to about 5xc2x0 C. below the melting temperature of the membrane polymer for a predetermined period of about 1-250 hours and subsequently incorporated into the delivery device.
The membrane material may be selected from the group consisting of ethylene vinyl acetate copolymers, polyethylene, copolymers of ethylene, polyolefins including ethylene oxide copolymers such as Engage(copyright) (DuPont Dow Elastomers), polyamides, cellulosic materials, polyurethanes, polyether blocked amides copolymers such as PEBAX(copyright) (Elf Atochem North America, Inc.), and polyvinyl acetate.
The device may be a transdermal drug delivery device comprising a drug reservoir layer between a backing layer and a contact adhesive layer, wherein rate controlling membrane is on the skin-proximal side of the drug reservoir layer. The drug reservoir may also contain one or more permeation enhancers and/or other excipients.
The device may be a transdermal drug delivery device comprising a backing layer, a permeation enhancer reservoir containing a permeation enhancer on the skin proximal side of the backing layer, a drug reservoir layer containing at least one drug to be transdermally administered on the skin proximal side of the permeation enhancer reservoir, and a means for maintaining said drug device in drug transmitting relation with the skin, wherein the rate controlling membrane is positioned between the permeation enhancer reservoir and the drug reservoir.
Alternatively, the membrane may be positioned in sealing relationship with an internal surface of one end of an impermeable reservoir of a fluid-imbibing drug delivery device, wherein the fluid imbibing drug delivery device comprises an impermeable reservoir containing a piston that divides the reservoir into a drug containing chamber and a water-swellable agent containing chamber, wherein the water-swellable agent containing chamber is provided with an outlet which accommodates the membrane. The agent containg layer may comprise leuprolide.
The membrane may be cooled to ambient conditions before being incorporated into the delivery device.
Additionally, the invention is directed to a method for processing rate controlling membranes used in controlled drug delivery devices comprising:
a) exposing the membrane to a predetermined temperature of from about 30xc2x0 C. to about 5xc2x0 C. below the melting temperature of the membrane polymer;
b) maintaining the membrane at the predetermined temperature for a period of time of from about 1 to 250 hours; and
c) incorporating said membrane into a controlled drug delivery device.
These and other aspects, features, and advantages of this invention will be more apparent from the following detailed description and drawings.